J . Org. Chem., Vol. 44, No. 24, 1979 4393
3-(Acylamino)- 3 - l x t a m i T o this solution, 0.5 mmol of a Cyt derivative, 8a,8c,18b, lac, or 5-bromo-1,3-dimethylcvtosine (381,in 0.3 mL of MeOH was added. This admixture was stirred for a period of time (see Table 11) and then evaporated until dry under reduced pressure at 22 "C. The residue was dissolved in acetone, and the product was precipitated by the dropwise addition of ethyl acetate. The precipitate was collected arid redissolved in acetone. Ethyl acetate was again added to the solution just prior to it becoming permanently cloudly. This clew solution was refrigerated, and the crystalline product was collected. Reaction conditions, results, and product properties alre given in Table 11. Preparation of 5-Brorno-6-hydroxy-5-methyl-5,6-dihydrocytosine (27)and 5-Broino-6-hydroxy-N4,5-dimethyl-5,6-dihydrocytosine (28). 5-Methylcytosine (39,1 mmol) in 3 mL of water was treated with 1.1 mmol of NBS. The mixture was stirred for 3 h and then refrigerated overnight. The crystalline product was collected. N4,5-Dimethylcytosine(40)was treated in a similar manner. However, 1 mL of water was used as solvent, and the reaction time required was 1 h. After lyophilization, the residue was triturated with CHC1, and the product isolated. Further information regarding the reactions and the products is presented in Table 11. Preparation of 5,5-Dib1romo-6-hydroxy-5,6-dihydrocytidine (9b), 5-Bromo-6-hydroxy1,N4-dimethyl-5,6-dihydrocytosine (20), 5,5-Dibromo-6-h>droxy-1,N4-dimethyl-5,6-dihydrocytosine (21), and 5-Bromo-6-hydroxy-l,N4,N4-trimethyl5,6-dihydrocytosirie(29). One millimole of 5-bromocytidine @b),
-
14V4-dimethylcytosine(18b),5-bromo-l,N4-dimethylcytosine (18c), and 1,iV4,N4-trimethy1cytotosine (41)in 10,2,1,and 0.3 mL of water, respectively, was treated with 1.1 mmol of NBS. The solution was stirred at room temperature for a period of time and then refrigerated overnight. The crystalline product was collected. [See Table I1 for additional infomation.]
Acknowledgment. The authors wish to t h a n k the early successful s t u d y m a d e b y M. Apicella and M. Mouyos. T h e NMR spectra were taken at the Middle Atlantic NMR Facility at t h e University of Pennsylvania in Philadelphia, under t h e supervision of Dr. George McDonald. This work was supported b y a g r a n t from the National Institutes of H e a l t h ( G r a n t No. 5 R01 GM24238). Registry No. 3a,51-20-7; 4a,1124-83-0; 6a,71-30-7; 6b,65-46-3; 8a,2240-25-7; baHBr, 71647-17-1; 8b,3066-86-2; 8c,65567-60-4; 9b, 71647-18-2; M a ,1122-47-0;18b,6220-49-1; 18c,71647-19-3; l813HB1, 71647-20-6; 20,71647-21-7; 21,71647-22-8; 22,71647-23-9; 23,7164724-0;24,71647-25-1; 25,71647-26-2; 26,71647-27-3; 27,71647-28-4; 28, 71647-29-5; 29, 71647-30-8;38, 64236-15-3;39, 554-01-8;40, 62006-34-2; 41,2228-27-5; bromine, 7726-95-6; ammonium bromide, 12124-97-9; NBS, 128-08-5.
Supplementary Material Available: Expanded version of Figure 5 showing additional time curves ( 2 pages). Ordering information is given on any current masthead page.
Phosphinimines as Useful Intermediates in the Synthesis of 3-(Acylamino)-&lactams Mario D. Bachi* a n d J a c o b Vaya Llepartment of Organic Chemistry, The Weizmnnn Institute of Science, Rehocot, Israel
ReceiLied J u n e 21, 1979
N-Substituted 3-azido-4-(methylthio)-2-azetidinones 9 (trans) and 10 (cis) reacted with triphenylphosphine to give the corresponding 3-phosphinimino-J-lactams 1 1 and 12. Treatment of these iminophosphoranes with phenoxyacetyl chloride afforded respectively the trans- and cis-3-(acylamino)-p-lactams 13 and 14. The cis-p-lactam 14 was obtainled also from the trans-6-lactam 11: condensation of 1 1 with p-nitrobenzaldehyde gave the Schiff base 19;kinetically controlled epimerization of 19, followed by hydrolysis and acylation. afforded the P-lactam 14.
The azido g r o u p has been used as a progenitor of t h e acylamino side chain in some total syntheses of penicillins,' cephalosporins,' a n d various analogues of these p-lactam tn these papers, 3-azidoazetidinones, rep~~
~~
resented b y t h e partial structure 1,were reduced b y cata-
~~~~~~
(1)R. A. Firestone, N. 5;. Maciejewicz, R. W. Ratcliffe, and B. G . Christensen, J . Org. Chem., 39,437 (19741,and references cited therein. (2)A. K. Bose, G. Spiegelmen, and M. S. Manhas, J . Am. Chem. Soc.. 90,4506 (1968). (3)L. D.Cama and B. G . Christensen, J . Am. Chem. Soc., 96,7582 (1974):Tetrahedron Lett.. 1233 (1978). (4)'R.N. Guthikonda, L.D. Cama, and B. G. Christensen, J . Am. Chem. Soc., 96,7584 (1974). ( 5 ) J. A. Edwards. A. Guzman, R. Johnson, P. J. Beeby. and H. H. Fried, Tetrahedron Lett., 2031 (1974). (6)A. K.Bose, G. Spiegelman, and M. S.Manhas, J . Chem. SOC.C. 2468 (1971). (7)M. D.Bachi a d 0. Goldberg, J . Chem. Soc.. Perkin Trans I . 2332 (1972). (8) R. Lattrel ana G. Lohaus. Justus Liebigs Ann. Chem., 901 (1974). (9)M. D. Bachi, N. Frydman, S. Sasson, C. Stern, and J. Vaya, Tetrahedron Lett., 641 (1977). (10)W.F. Huffman, K. G . Holden, T. F. Buckley 111, J. G. Gleason, and L. u'u, J . Am. #?hem.Sot., 99,2353 (19771,and subsequent paper in the same series.
0022-3263/79/1944-4393$01.00/0
1, R = N, 2, R = NH, 3, R = R'CONH 4, R = Ph,P=N 5, R = p-O,NC,H,CH=K
lytic hydrogenation, hydrogen sulfide i n t h e presence of a m m o n i a or triethylamine, or zinc in acetic acid t o the corresponding 3-aminoazetidinones 2. Compounds 2 were subsequently converted into 3-(acy1amino)azetidinones 3. (11) T.T.Conway, G. Lim, J. L. Douglas, M. Menard, T. W. Doyle, P. Rivest, D. Horning, L. R. Morris, and D. Cimon, Can. J . Chem., 56, 1335 (19781,and previous papers in the same series. (12) P. J. Claes, G. Janssen, and H. Vanderhaeghe, E m . J . Med. Chem.-Chim. Ther., 521 (1977),and references cited therein.
1979 American Chemical Society
Bachi and Vaya
4394 J Org Chem , Vol 44, No. 24, 1979
Despite the successful use of this simple reaction sequence, it cannot be considered of general applicability. In fact, in at least one case a different reaction pattern has been reported.13 More difficulties are to be expected on extending this procedure to the synthesis of 0-lactams which exhibit a particularly high chemical activity toward nucleophilic agents. The ability of P-lactams to acylate nucleophiles has been correlated to their antibacterial activity and has been taken into consideration in the design of new antibiotic^.'^ It was therefore felt that a method for the conversion of 3-azidoazetidinones 1 into 3-(acylamino)azetidinones 3 which avoids the intermediacy of compounds having a free amino group may, in certain cases, be advantageous. A synthetic route of this kind, which is based on the intermediacy of phosphinimines of type 4, is described in the present paper. Compounds 4 also proved to be useful synthetic precursors of Schiff bases 5 which were employed for the “correction” of the stereochemistry of the P-lactam ring according to the Merck procedure.’ The substrates for the present investigation were nonfused P-lactams which, like the natural penicillins and cephalosporins, bear a carboxylic (or an ester) group on the carbon atom attached to the ring nitrogen atom, a nitrogen substituent at the 3-position, and a sulfur substituent at the 4-position. This type of compound can be obtained by building the azetidinone on the nitrogen atom of a-aminocarboxylic acids.15 To avoid the introduction of an additional c h i d center, we chose a-aminoisobutyric acid as a model. Condensation of a-aminoisobutyric acid with 0-ethyl thionoformate gave the thioformamide 6 (42% ). Esterification of 6 with diphenyldiazomethane afforded 7 (68% ) which was S-methylated with methyl iodide and potassium carbonate to give the thioformimidate 8 (96%). Reaction Me
HCSNH
4
Me
SMe
Me
I
HC=N+Me C O 2CHPh 2
C02R
6, R. = H 7, R. = CH:Ph,
8
yield based on 9. The cis isomer 12 was similarly converted into 14 (62%). This method was found to be effective also with compounds bearing a free carboxylic group in place of the ester grouping. Thus, treatment of 9 with trifluoroacetic acid and anisole afforded the acid 15 (89%). Addition of triphenylphosphine to 15 in chloroform afforded the phosphinimine 16 which was treated with phenoxyacetyl chloride and triethylamine to give, after workup with aqueous potassium bicarbonate, the (acylamino)-&lactam 17 (44%). Esterification of 17 with diphenyldiazomethane gave 13 which was identical with the compound obtained as previously described in the sequence 9 11 13. The acid 16 was obtained also on treatment of 11 with trifluoroacetic acid. The reaction of triphenylphosphine and alkyl azides which results in the formation of N-alkylphosphinimines is well d~cumented.’~J~ On the other hand, there are only a couple of references to the reaction of acyl halides with N-alkyl tertiary phosphinimines. In these papers imidoyl halides 18 were obtained.18J9 It is possible that the transformations of 11 to 13 and 12 to 14 involved the intermediacy of imidoyl chloride derivatives of type 18 which were hydrolyzed during the workup to the respective amides 13 and 14. A very lowyield conversion of a 7-azido-7-methoxycephem into a 7methoxycephalosporin system, involving the intermediacy of a phosphinimine, has recently been reported.20 A major drawback in the synthesis of P-lactam antibiotics, or their nuclear analogues, by the method based on the cycloaddition of azidoacetyl chloride to the C=N bond of a thiazoline,’~*J2thiazine,’ or other thioformimidates7p8 lay in the resulting trans stereochemistry of the nitrogen and sulfur substituents. To obtain the cis stereochemistry as found in the natural products, the Merck group developed a method for the kinetically controlled isomerization of 6a-aminopenicillins and 7a-aminocephalosporins to their 0-epimers.l This procedure, which has so far been applied to bicyclic systems, proves now to be effective also with nonfused P-lactams. Thus, the reaction between the phosphinimine 11 and p-nitrobenzaldehyde afforded the Schiff base 19 (87%) and triphenylphosphine oxide.
--
R+ I
C02CHPh2
9, R = N, 11, R = Ph,P=I\r 13, R = PhOCI[,CONH
602 C HPh 2
10, R = N, 12, R = Ph,P=N 14, R = PhOCH,CONH
of 8 with azidoacetyl chloride in the presence of triethylamine afforded, after chromatography, the trans-p-lactam 9 (83%) and the cis-p-lactam 10 (6%). The reaction between 2-heterosubstituted acetic acid chlorides, including azidoacetyl chloride, and S-alkylthioformimidates has been known to give exclusively t r ~ n s - ~ - l a c t a m sthe ; ~ ~forma~J~ tion of 10 constitutes the first case, in which a cis-p-lactam was obtained directly from a thioformimidate. The azides 9 and 10 were converted into the corresponding iminophosphoranes 11 and 12 with triphenylphosphine. Treatment of 11 with phenoxyacetyl chloride followed by aqueous workup gave the truns-(acylamino)-p-lactam13 in 75% (13) M. S. Manhas, J. S. Chib, and A. K. Bose, J . Org. Chem., 38, 1238 (1973). (14) See, for example, the synthesis of penems: I. Ernest, J. Gosteli, C. W. Greengrass, W. Holick, D. E. Jackman, H. R. Pfaendler, and R. B. Woodward, J. Am. Chenz. Soc., 100, 8214 (1978). (15) M. D. Bachi and K. J. Ross-Petersen, J . C h e n . Soc., Perkin Trans. 1, 2525 (1975), arid references cited therein.
SMe
X
Q$
C 0 2 H Me
0
15, R 16, R 17, R
= = =
RC=NR’ 18
N, Ph,P=N PhOCH,CONH R 2I
b;eMe
0
C02CHPh 2
19, R’ = H; R 2 = p-NO,C,H,CH=N 20, R’ = Li; R 2 = p-NO,C,H,CH=N 21, R’ = p-NO,C,H,CH=N; R 2 = H 22, R’ = H ; R z = NH, 23, R’ = NH,; R Z = H (16) G. Singh and H. Zimmer, Organomet. Chem. Reu., 2,279 (1967). (17) A. W. Johnson, “Ylide Chemistry”, Academic Press, New York and London, 1966, Chapter 6. (18) E. Zbiral and E. Bauer, Phosphorus, 2, 35 (1972). (19) T. Hiraoka, K. Iino, Y. Iwano, T. Saito, and Y. Sugimura, Chem. SOC.,Spec. Publ., No. 28, 126 (1977). (20) T. Hiraoka, Y. Sugimura, T. Saito, and T. Kobayashi, Heterocycles, 8, 719 (1977).
3-(Acylamino)-~-lactams
Treatment of 19 in ether with phenyllithium gave the lithium derivative 20. :Protonation of 20 under kinetically controlled conditions afforded a 1:lmixture of the trans8-lactani 19 and the cis-a-lactam 21. In the epimerization of benzyl 6~-(P-nitrobenzylideneamino)penicillanate, a 1:2 trans to cis ratio was reported.' The rigid five-membered ring fused to the 6-lactam moiety in the penicillin system is obviously a better control element than the smaller, freely rotat.ing, inethylthio group in 20. Treatment of i;he mixture of 19 and 21 with 2,4-dinitrophenylhydrazine and ptoluenesulfonic acid gave a mixture of the ti.ans- and cis-aminoazetidinones 22 and 23 which were acylated with ph'enoxyacetyl chloride. Chromatography of the mixture g,sve the trans-(phenoxyacetamin0)azetidirione 13 (39%) iind its cis isomer 14 (38%). These compounds were identical with the products of direct acylation of the respective phosphinimines 11 and 12.
Experimental Section 2-(Thioformylamino~~isobutyric Acid (6). To a solution of 2-aminoisobutyric acid (1.0.3g, 0.1 mol) in chloroform (300 mL) which was saturated at C " C with hydrogen sulfide were added triethylamine (18.1 g, 0.18; mol) and ethyl thionoformate (20 mL). The mixture was kept for 16 h at room temperature and then evaporated. The residue vias taken up with water (100 mL), mixed with ethyl acetate (200 mL), and acidified with 3 N hydrochloric acid to pH 3. The aqueous phase was extracted with ethyl acetate, and the combined xganic fractions were washed with water, dried (MgSO,), and evaporated. The residue was crystallized from ether to give :he thiofoxniamitie 6 (6.1 g, 42%): mp 84-85 "C; NMR [(CD3)2C"and D@] F 1 62 (s) and 1.66 (s) (6 H), 9.3 (br, 1 H). Anal. Calcd for C&NO,?S: C. 40.81; H, 6.17. Found: C, 40.65; H , 6.26. Diphenylmethyl2-(7'hioformylamino)isobutyrate(7). To a solution of the acid 6 ( 5 . 5 g, 37.4 mmol) in dry acetone (100 mL) was added a solu1,ion of diphenyldiazomethane in acetone (40 "01). After 2 h, the mixture was evaporated, and the residue was triturated with ether and then crystallized from CHZClzhexane to give the ester 7 (8.0g, 68%): mp 112-114 "C; IR (KBr) 3300, 1720, 1540 cin-'; NMR (CDCl,) b 1.58 (s, 6 H), 6.90 (s, 1H), 7.30 (s, 10 HI, 8.30 (br, 1 €I),9.30 (d, 1 H, J = 14 Hz). Anal. Calcd for C1xHlsNOzS:,?, 68 1: N,4.47; S, 10.21. Found: C, 68.88; H,6.26; N: 4.40 Methyl N - [1-((Di e t hoxy)carbonyl)- 1-met hylethyl]thioformiinidate (8). To a stirred mixture of the thioformamide ? (1g. 3.11 inniol) and potassium carbonate (0.5 g, 3.6 mmol) i n acetone I30 ml,! was added methyl iodide (0.9 g, 5.76 mmol). Stirring was continued for 16 h, the salts were filtered off. and the filtrai e was evaporated to give the thioformimidate 8 ( 1g, 96% ): IR tCHC1,) 1730, 1590 cm-'; NMR (CDCl,) 6 1.43 is, 6 H ) , 2.23 is, i H i . 6.78 (s. 1 H), 7.25 (9, 10 H), 8.1 (s, 1 H). This compound "as used in the next step without further purification 4-Azido-1-[1~ l(dipheny1methoxy)carbonyl)I 1-methylethy1]-4-(methyilthio)-Z-azetidinones 9 a n d 10. To a stirred solution of the thioforxriimidate 8 (6.8 g, 20.7 mmol) and trimmol) in toluene (200 mL) was added a 1 chloride (3.58 g, 30 mmol) in toluene (150 mL) under an argon atmosphere during 6 h. After an additional 12 h, another portion of t.riethylamine (3.2 g, 32 "01) was added followed by a second dropwise addition (6 h) of a solution of azidoaccityl chloritic: (,3.5Fi g, 30 mmol) in toluene (150 mL). After an additional 16 h , the mixture was filtered through Celite, evaporeted, and I:hromtitographed (silica gel, hexane-acetone) to give B mixture of the trans and cis isomers 9 and 10. Cryst,allization from ether afforded the trans isomer 9 (7.1 g, 83%): mp 80 '12; IK (CHCI;j) 2110, 1775, 1735 cm-'; NMR (CDC13)6 1.70 (s, 3 H ) . 1.75 (s, 3 El), 1.!16 (s, 3 H), 4.52 (d, 1 H, J = 2 Hz), 4.63 (d. I H , J = 2 Hz:.'i.O3 Is, 1 H), 7.43 (s, 10 H); MS m / e 382 (M' - Nz). iinal. Calcd for C.'1H22N403S: C, 61.44; H, 5.40; N, 13.65; S,7.81. Found: (1, 6:L.Z; H, 5.55; N, 14.05; S, 8.12. Evaporation of the filtrate fol'owed 11y chromatography gave the cis isomer 10 (0.5 g, 6%): Jil; 1R (CHCl,) 2105, 1770, 1735 cm-'; NMR (CT>Clq'6 1..67 ( s . :I HI. 1 72 (s. 3 H), 1.97 (s, 3 H), 4.66 (d, 1 H,
J . Org. Chem., Vol. 44, No. 24, 1979 4395 J = 5 Hz), 4.83 (d, 1 H, J = 5 Hz), 6.86 (s, 1 H), 7.26 (9, 10 H); MS m / e 382 (M' - Nz). Acidolysis of the Diphenylmethyl Ester 9. To a solution of the ester 9 (200 mg, 0.49 mmol) in anisole (0.2 mL), a t 0 "C under argon, was added trifluoroacetic acid (2 mL). After 5 min the trifluoroacetic acid was removed under reduced pressure, and the residue was taken up with chloroform and then extracted with 4% aqueous KHC03. The aqueous fraction was acidified with phosphoric acid to pH 2.5 and extracted with chloroform. The solution was dried (MgSO,) and evaporated to give the free acid 15 (106 mg, 89%): IR (CHC13) 2110, 1765, 1715 cm-'; NMR (CDClJ 6 1.71 (9) and 1.75 (s) (6 H), 2.20 (s, 3 H), 4.62 (d, 1 H, J = 1.5 Hz), 4.81 (d, 1 H, J = 1.5 Hz),9.97 (9, 1 H). 3-Phosphinimino-2-azetidinones 11, 12, a n d 16. A. To a solution of the azido lactam 9 (200 mg, 0.49 mmol) in benzene (4 mL) was added triphenylphosphine (133 mg, 0.5 mmol). After 15 min the solution was evaporated, and the residue was crystallized from ether to give the phosphinimine 11 (300 mg, 90%): mp 132 "C; IR (KBr) 1765, 1730 cm-'; NMR (CDC13) 6 1.58 (s, 3 H), 1.71 (9) and 1.75 (s) (6 H), 4.33 (dd, 1 H, J = 1.5 and 26 Hz), 4.66 (d, 1 H, J = 1.5 Hz), 7.01 (s, 1 H), 7.25-8.12 (m, 25 H). Anal. Calcd for C&37N203SP: C, 72.68; H, 5.74; N, 4.35; S, 4.97. Found: C, 72.65; H, 5.78; N, 4.45; S, 5.13. B. The azidolactam 10 was treated with triphenylphosphine as described in A for its isomer 9 to give the phosphinimine 12 (quantitative): NMR (CDCIJ 6 1.67 (9, 3 H), 1.85 (8, 3 H), 2.22 (s, 3 H), 4.70 (dd, 1 H, J = 4.5 and 28 Hz), 4 75 (d, 1 H, J = 4.5 Hz), 7.0 (s, 1 H), 7.3-8.2 (m, 25 H). C. To a solution of the azidolactam 15 (150 mg, 0.61 mmol) in chloroform (5 mL) was added triphenylphosphine (162 mg, 0.61 mmol). After 30 min the solution was evaporated and the residue washed with benzene to give the phosphinimine 16 (286 mg): oil; IR (CHCl,) 1760 cm-' (br), no absorption band for N,; NMR (CDC13) 6 1.42 (9) and 1.55 ( S I (6 H), 1.83 (s, 3 H), 3.83 (dd, 1 H, J = 2.0 and 14 Hz), 5.37 (d, 1 H, J = 2.0 Hz), 7.19-8.16 (m, 15 H), 8.38 (br s, 1 H). D. The trifluoroacetate of 16 was obtained by an alternative way. To a solution of the phosphinimine 11 (100 mg, 0.15 mmol) in anisole (0.3 mL), at 0 "C under argon, was added trifluoroacetic acid (2 mL). After 5 min the mixture was evaporated under reduced pressure, and the residue was triturated with ether to give the trifluoroacetic acid salt of 16 (76 mg, quantitative): NMR (CDC1,) 6 1.55 (9) and 1.59 (s) (6 H), 1.78 (s, 3 H), 3.83 (br) and 4.03 (br) (1H), 5.19 (br, 1H), 7.5S8.08 (m, 15 H), 8.98 (br). Anal. Calcd for C,8Hz8Nz05F3SP:(2, 56.75; H, 4.76. Found: C, 56.65; H, 4.62. trans-1-[ 1-((Dipheny1methoxy)carbonyl)-1-methylethyl]-l-(methylthio)-3-( phenoxyacetamido)-2-azetidinone (13). To a solution of 11 [prepared as described in the previous section from 100 mg (0.24 mmol) of 91 in CHZClz(4 mL), at 0 "C, was added a solution of phenoxyacetyl chloride (39 mg, 0.23 mmol) in CH2Cl2 (0.5 mL) during 15 min. After E h a t 0 "C and an additional 1 h at 25 "C, a solution of 4% aqueous KHC03 was added with stirring. Stirring was continued for an additional 20 min, and then the organic layer was washed with water, dried (MgSO,), and evaporated. Crystallization of the residue (ether) gave the title compound 13 195 mg, 75% from 9): mp 115-117 "C; IR (KBr) 1770,1730,1660 cm-'; NMR (CDC13)6 1.73 (9) and 1.75 (s) (6 H), 2.0 (9, 3 H), 4.31 (s, 2 H), 4.69 (d, 1 H, J = 2 Hz), 4.85 (dd, 1H, J = 2 and 8 Hz), 6.88 (s) and 7.38 (s) and 6.80-7.50 (m) (16 H). Anal. Calcd for C29H30N205S: C, 67.16; H , 5.83; N, 5.40; S, 6.18. Found: C, 67.05; H, 5.90; N, 5.54; S, 6.28. cis-1-[1- ((Diphen ylmet hoxy )carbon yl) - 1-methylet hyll-4(methylthio)-3-(phenoxyacetamido)-2-azetidinone (14). T o a solution of 12 (127 mg, 0.2 mmol) in CHzCl2(5 mL) was added a solution of phenoxyacetyl chloride (34 mg, 0.20 "01) in CHZCl2 (0.5 mL) at 0 "C during 15 min. The product obtained after workup as described above for the preparation of 13 was chromatographed (silica gel, hexaneacetone) to give the title compound 14 (62 mg, 62%): oil; IR (CHCl,) 1770, 1740, 1685 cm-'; NMR (CDClJ 6 1.67 (s) and 1.73 (s) and 1.78 (9) (9 H), 4.59 (s, 2 H), 4.86(d,lH,J=4.5),5.60(dd,lH,J=4.5and9.5H~),6.83-7.50 (m) and 7.35 (s) (16 H). Anal. Calcd for CaHHNZO5S: C, 67.16; H, 5.83; N,5.40; S, 6.18. Found: C, 67.15; H, 5.91; N, 5.20; S, 5.92. Compound 14 was obtained also from the trans-lactam 11 as described in the last section.
Boeckman e t al.
4396 J. Org. Chem., Vol 44, No 24, 1979 1-(1-Carboxy - 1-methylet hy1)-3-(methy1thio)-4-(phenoxyacetamido)-2-azetidinone (17). To a solution of the phosphinimine 16 (87 mg, 0.18 mmol) and triethylamine (40 mg, 0.4 mmol) in CHzClz(3 mL), a t 0 "C under argon, was added a solution of phenoxyacetyl chloride (34 mg, 0.2 mmol) in CHzClz (0.5 mL) during 10 min. After 2 h a cold 4% aqueous KHC03 solution was added with stirring. The organic phase was extracted with water, and the combined aqueous extracts were mixed with ether and then acidified to pH 2.5 with 10% H3P04. The aqueous fraction was extracted with ether, and the combined etheral fractions were dried and evaporated to give the title compound 17 (28 mg, 44 %): oil; IR (CHC13) 1760, 1710, 1680 cm-'; NMR (CDClJ 6 1.70 (9, 6 H), 2.19 (s, 3 H), 4.54 (s, 2 H), 4.90 (m, 2 H), 6.0 (br, 2 H), 6.7-7.8 (m, 5 H). Treatment of a sample of 17 in CHZCl2with diphenyldiazomethane in acetone gave the diphenylmethyl ester 13,identical in its physical data with an authentic sample prepared as described in a previous section. Conversion of the tram-Azidolactam 9 to the cis-(Acylamino)lactam 14 through the Intermediacy of 11,19,20,21, and 23. To a solution of 11 obtained as previously described from 164 mg (0.4 mmol) of 9, in benzene (4 mL) was added p-nitrobenzaldehyde (65 mg, 0.43 mmol). After 2 h the mixture was evaporated under reduced pressure, and the residue was washed with ether to give the Schiff base 19 (180 mg, 87%): oil; IR (CHCl,) 1760, 1'740, 1630 cm-'; NMR (CDClJ 6 1.76 (s) and 1.80 (s) (6 H), 2.04 ( 3 , 3 H), 4.77 (d, 1 H, J = 2 Hz), 5.00 (d, 1 H, J = 2 Hz), 6.93 (s, 1 H), 7.37 (br s, 10 H), 7.88 (d, 2 H, J = 9 Hz), 8.25 (d, 2 H, J = 9 Hz) 8.57 (s, 1 H). To the Schiff base 19 (150 mg, 0.29 mmol) in THF (4 mL), under argon at 4 8 "C, was added a solution of PhLi (0.29 mmol) in ether. After 5 min, DMF (5 mL) was added followed by an immediate quenching with a solution of AcOH (0.3 mL) and H 2 0 (0.3 mL) in T H F (2 mL). The reaction mixture was brought to room temperature and then
diluted with benzene (20 mL) and washed with water, pH 4.4 buffered phosphate solution, pH 8 buffered phosphate solution, and again water. The NMR spectrum of the residue obtained after drying and evaporation indicated the presence of a 1:l mixture of the Schiff bases 19 and 21. NMR (CDClJ of 21: 6 1.74 (s), 1.80 (s), 2.00 (s), 5.04 (formal 4). The p-nitrobenzylidene grouping was removed from 19 and 21 with 2,4-dinitrophenylhydrazine (60 mg, 0.3 mmol) and p-toluenesulfonic acid (59 mg, 0.3 mmol) in ethanol (4 mL),' to give a mixture of the amines 22 and 23. To a solution of the crude product and triethylamine (37 mg, 0.37 mmol) in CH2Cl2,under argon a t 0 "C, was added a solution of phenoxyacetyl chloride (51 mg, 30 mmol) in CHzClz (0.5 mL) during 15 min. After another 2 h the mixture was washed with 5% aqueous H3P04,4% aqueous KHC03, and water, dried, and evaporated. The NMR spectrum of the residue indicated the presence of a 1:l mixture of 13 and 14. Treatment of the product with ether resulted in the crystallization of 13 (48 mg). The mother liquor was evaporated, and the residue was chromatographed on a silica gel plate (hexane-acetone) to give 14 (56 mg, 38% yield based on 21) and a second portion (12 mg) of 13. The spectral data of these samples of 13 and 14 were identical with those of the fully characterized compounds described in previous sections. Registry No. 6, 71537-37-6; 7, 71537-38-7; 8, 71537-39-8; 9, 71537-40-1; 10, 71537-41-2; 11, 71537-42-3; 12, 71537-43-4; 13, 7153744-5; 14, 71537-45-6; 15, 71537-46-7; 16, 71565-59-8; 16 trifluoroacetate salt, 71565-60-1; 17,71537-47-8;19,71537-48-9:21, 71537-490; 22, 71537-50-3;23, 71537-51-4; 2-aminoisobutyric acid, 62-57-7; ethyl thionoformate, 29392-46-9;diphenyldiazomethane, 883-40-9; azidoacetyl chloride, 30426-58-5;trifluoroacetic acid, 354-32-5;triphenylphosphine, 603-35-0; phenoxyacetyl chloride. 701-99-5; p nitrobenzaldehyde, 555-1643,
Diels-Alder Cycloaddition of Juglone Derivatives. 2. Regiospecificity of Reactions Leading to Tetracyclic Anthracyclinone Systems' Robert K. Boeckman, Jr.,*2 Mary H. Delton, Terence M. Dolak, Tokuhiro Watanabe, and Milton D. Glick Department of Chemistry, W a y n e State Uniuersity, Detroit, Michigan 48202
Received M a y 30, 1979 The regicispecificity of the reaction of several juglone derivatives with two complex dienes derived from bicyclic dimethoxycyclobutenes has been examined as part of a series of model studies leading toward the synthesis of the anthracyclinone antibiotics adriamycin and daunorubicin. In general, regiospecificity appears governed primarily by diene polarization factors. The structural assignments have been confirmed by a single-crystal X-ray analysis of one of the tetracyclic adducts from juglone methyl ether and related by chemical interconversion.
The development of synthetic approaches to the anthracyclinone class of antitumor antibiotics has been the object of intense study by a number of research groups in this country and abroad. The clinical importance of adriamycin (11 and to a lesser extent daunorubicin (2) as antitumor agents has been a major stimulus of this activit^.^ In addition, though, the unreliability of biochemical sources of the active substances4 and the discovery of significant and potentially severe side effects, especially acute cardiac toxicity resulting from therapeutic administration of 1 and 2, have further encouraged the exploration of ~ (1) For previous studi'es see: Boeckman, Jr., R. K.; Dolak, T. M.; Culos, K. 0. J . Am. Chert Soc. 1978, 100, 7098. (2) (a) Fellow of the Alfred P. Sloan Foundation, 1976-1980. (b) Recioient of a Career Devdooment Award (CA-00273) from the National Cancer Institute of the Katjonal Institutes of Health (1976-1981). (3) Henry, D. W. ACS Symp. Ser. 1976, No. 30. (4) Arcamone, F.; CassInelli, G.; Fantini, G.; Grein, A,; Oremi, p.; pol, P.; Spalla, C. Btotech. Biwng. 1969, 11, 1101.
methods to prepare not only 1 and 2 but a variety of analogues which are unavailable by chemical modification of 1 and 2.
:ti30
-+OH
B I
\
\
c
1
t-0
--c -
rlh2
.is 3
CH3
1, R = OH 2,R=H
The total synthesis of 1 and related systems poses three independent problems: (1)aglycone synthesis, (2) synthesis of the requisite carbohydrate, and (3) methodology for
0022-3263/79/1944-4396$01.00/0 0 1979 American Chemical Society
